Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.

ABSTRACT: Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule KRAS inhibitors have emerged as promising cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated wit

SUBMITTER: Paulsohn MB 

PROVIDER: S-EPMC12847887 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature